The role of the pineal gland and its hormone, melatonin, has been difficult to define in humans, because the circulating levels of melatonin have been too low to measure. In collaboration with Dr. S. Markey of the LCS, we have developed a highly sensitive and specific gas chromatographic-mass spectrometric (GC-MS) assay which requires less than 1 ml of human plasma, CSF, or urine. We are currently investigating: (1) the circadian pattern of secretion of melatonin in normal individuals and its alteration in a variety of disease states (such as depression, mania, and blindness); (2) the relationship between melatonin secretion and other circadian rhythms; (3) the effect of drugs on melatonin secretion; (4) the effect of different intensities of light on melatonin secretion; and (5) the use of basal and isoproterenol-stimulated melatonin levels to assess beta-adrenergic receptor function. We have found a phase shift of the usual circadian secretory pattern in affectively-ill patients and a significantly disrupted pattern in blind individuals. Tricyclic antidepressants produce changes in melatonin secretion which are consistent with alterations in both pre- and post-synaptic beta-adrenergic functioning. There is a "dose-response" relationship between the intensity of light administered in the early morning hours and the resultant suppression of melatonin secretion.